The peak circuit turns, the clouds are cleared| mCRC patients are failing in the first- and second-line standard treatment, and the third-line precision treatment is turning things around

In recent years, with the continuous development and advent of targeted drugs and immune drugs, the means of tumor treatment have become more and more abundant, and the survival time of advanced tumor patients has been continuously extended
.
In the field of colorectal cancer (CRC), new breakthroughs and advances have been made in targeted therapy and immunotherapy, especially for patients with MSI-H/dMMR (microsatellite highly unstable/mismatch repair gene defects) type CRC, immunotherapy has benefited
significantly.
However, MSI-H/dmmR patients account for only 5 percent of all CRC patients, and the remaining 95 percent of MSS/pMMR (microsatellite stable/mismatch repair gene intact) CRC patients are almost insensitive to immunotherapy ^[1], and treatment was once in trouble
.

With the continuous deepening of clinical research, small sample studies of small molecule antiangiogenic targeted drugs combined with immune checkpoint inhibitors have achieved good efficacy in the treatment of patients with MSS type advanced CRC, but the screening of beneficial populations is still being
studied in depth.
For patients with MSS advanced CRC who cannot benefit from immunotherapy, the choice and choice of regimen have become difficult points in clinical practice
.
Taking this opportunity, the Colorectal Cancer Committee of the Chinese Society of Clinical Oncology and Hutchison Pharmaceutical jointly held the 2022 "YOUNG Good Medical Voice - Presentation on the Whole Process Management of Advanced Colorectal Cancer" activity
.
A number of clinical front-line doctors shared classic and difficult cases, and many experts participated in the summary and commentary, providing certain references and references
for follow-up CRC diagnosis and treatment.
During the speech event, Dr.
Liu Shuhan from the Cancer Center of the First Affiliated Hospital of Jilin University from Northeast and Northwest Station brought a case of "Thinking in Action, Turning the Peak, Turning the Clouds and Seeing the Sun - A Case of Multi-line Treatment of Bowel Cancer and Liver Metastasis", and shared her experience and thinking
as a clinical front-line doctor in the diagnosis and treatment management of patients with metastatic colorectal cancer (mCRC).

Case review

▎Basic information

• Female patient, 66 years old;

• Current medical history: On July 3, 2020, the patient developed "intermittent right upper quadrant pain with intermittent blood in the stool for 4 months", so he came to our hospital for treatment;

• Anamnesis: history of angina, coronary stenting for 2 months; The rest of the basic medical history and family history are not special;

• Physical examination: tenderness in the right upper abdomen, no rebound tenderness and muscle tension, palpable a 5cm*5cm ligament mass;

• Laboratory test tips: CA199: 49.
  13 U/mL; CEA：22.
  43ng/mL； Hemoglobin: 87g/L; There were no obvious abnormalities in blood biochemistry;

• Colonoscopy suggests: a mass with ulcer can be seen in the colonic liver area, the size of the mass is 6cm*5cm, the surrounding embankment is raised, and it is easy to bleed to the touch, and colorectal cancer
  is considered.
  Pathological suggestion: moderately differentiated adenocarcinoma;

• CT suggests: colonic liver curvature mass lesions, the lesion and adjacent peritoneum and duodenal demarcation is not clear, with multiple surrounding small lymph nodes;

Figure 1 CT image

▎Diagnosis and treatment

• After admission, the patient completed the relevant preoperative examination, ruled out contraindications to surgery, and underwent radical colectomy on July 5, 2020.
  

• Postoperative pathological suggestion: differentiated adenocarcinoma in the colon, tumor size of 6cm*5.
  5cm*2.
  8cm, invasion of subserosal connective tissue, visible vascular and nerve invasion
  .
  No cancer was seen at the two margins, cancer was visible on the serous side, no cancer was seen in the connected omentum, no cancer was seen in the appendix, and cancer metastasis was visible in the periintestinal lymph nodes (1/22); Distribution (duodenal wall) may show colon adenocarcinoma involvement; Distribution (omentum) no cancer;

• Immunohistochemistry: colon tumors: Ki-67 (+60%), MLH1 (+> 90%), MSH2 (+>90%), MSH6 (+>90%), PMS2 (+> 90%), P53 (+> 90%), intraduodenal tumors: Ki-67 (+80%), CDX-2 (+), CK20(+), CK7(-), P53 (+> 90%);

• Postoperative pathological stage: T4bN1a (AJCC 2017);

▎Disease diagnosis

Differentiated adenocarcinoma of the colon (cT4bN1bM0, stage III.
B), MSS;

▎Efficacy evaluation

CT reexamination one month after surgery showed that the liver had multiple masses (10), which was new compared with preoperative CT, and metastases
were considered.
Perfect genetic detection showed that the KRAS gene exon 2 had a point mutation, and no target mutations of NRAS, BRAF and PIK3CA genes were detected.

▎First-line treatment (August 5, 2020 - January 15, 2021)

After discussion by the multidisciplinary team (MDT), multiple liver metastases occurred 1 month after surgery, and there are currently about 10 liver metastases, ranging in size, scattered distribution, and lack of local treatment conditions
.
At the same time, based on the patient's double lower limb venous thrombosis and only 4 weeks after surgery, bevacizumab was not used;

Table 1 First-line treatment process and efficacy evaluation table

Fig.
2 Comparison of CT images for second-line therapy

▎Second-line treatment (January 15, 2021 - March 8, 2021)

Treatment evaluation: After discussion of MDT, the patient's efficacy after chemotherapy is not good, and the second-line standard treatment regimen is recommended according to the CSCO colorectal cancer guidelines;

Treatment regimen: FOLFIRI (ilinotecan + oxaliplatin) chemotherapy combined with bevacizumab for 3 cycles;

Adverse reactions: thrombocytopenia of degree II, granulocytopenia of degree II (improvement after symptomatic treatment);

Efficacy evaluation: enlargement of target lesions in the liver indicates PD;

Fig.
3 Comparison of CT images for second-line therapy

▎Third-line treatment (March 8, 2021 - March 8, 2022)

Treatment evaluation: the patient has not benefited from second-line therapy as discussed in MDT, and may benefit from PD-1 immunosuppressants based on the patient's genetic testing with co-occurring TP53 and KRAS mutations ^[2].

According to the CSCO colorectal cancer guidelines, fruquintinib in the third-line standard treatment regimen is recommended, and the treatment plan for anti-angiogenic combined immunity is finally selected;

Treatment regimen: fruquintinib + cindilimab 14 cycles;

Efficacy evaluation: regular review in the middle, liver target disease continued to shrink, indicating disease remission (PR), until March 8, 2022, the liver target lesion enlarged, suggesting PD;

Fig.
4 Third-line treatment CT image evaluation

▎Fourth-line treatment (March 8, 2022 - May 17, 2022)

Treatment evaluation: the patient's benefit time from third-line treatment was 12 months, and the target lesion of the liver appeared enlarged on March 8, 2022, and the patient was generally stable, so he was replaced with fourth-line therapy;

Treatment regimen: TAS-102 combined with bevacizumab for 2 cycles;

Adverse reactions: second-degree granulocytopenia (improvement after symptomatic treatment);

Efficacy evaluation: the target lesion in the liver is enlarged, and new lesions appear in the lungs, indicating PD;

Follow-up treatment: it is recommended to treat with envolimab in combination with regorafenib, unfortunately, the patient died of sudden convulsions 1 week later;

Fig.
5 Evaluation of CT images for fourth-line therapy

Expert reviews

Instructor: Professor Wang Yizhuo, First Hospital of Jilin University

Expert comments: Professor Zhao Junhui, Cancer Hospital of Qinghai University

Professor Wang Yizhuo, the supervisor, added to the selection of third-line treatment: after comprehensive consideration of the patient's clinical characteristics, previous treatment response, and NGS test results, it was decided to break the traditional treatment mode and choose anti-angiogenic combined immunotherapy for patients, which has a significant
effect.
The therapeutic benefit of this patient suggests that antiangiogenic combined immunotherapy has certain effectiveness and promising prospects in
MSS-type mCRC.

At the 2021 American Society of Oncology Clinical Society (ASCO) annual meeting, the data of a phase Ib study of fruquintinib combined with sindilimab led by Professor Jin Li showed that the objective response rate (ORR) and disease control rate (DCR) of fruquintinib (5mgQD, 2 weeks, 1 week of withdrawal) combined with sindilimab (200mgQ3 weeks) was 27.
3% and the disease control rate (DCR) was 95.
5%.
The median progression-free survival (mPFS) is 6.
9 months, and it is generally safe and well tolerated ^[3].

This study suggests that antiangiogenic combined immunotherapy is effective in MSS type advanced CRC, and the excellent efficacy of this protocol has been fully demonstrated
in the above real-world cases.

Professor Zhao Junhui from the Cancer Hospital of Qinghai University also commented on the patient's third-line treatment options: the entire third-line treatment is the most exciting and bright part of this case, and the benefits from the patient are due to the standardized, precise and individualized diagnosis and treatment plan
.
In a prospective clinical study of lung adenocarcinoma in which Professor Wu Yilong participated, PD-1 immunosuppressants were shown to be of significant clinical benefit in patients with both TP53 and KRAS mutations ^[2].

In view of the fact that the patient also had the above mutations, Dr.
Liu Shuhan also combined immunotherapy on the basis of third-line standard treatment and obtained PFS
for 12 months.
Although the final patient was PD, the PFS obtained in the third-line therapy accounted for more than half of the total PFS, which also highlighted the good benefit
of anti-angiogenic combined immunotherapy for this patient.

In general, this case suggests that in the actual clinical diagnosis and treatment, doctors should carry out standardized, whole-process and individualized diagnosis and treatment management
on the basis of evaluating the effectiveness and safety of treatment options.
At the same time, it is also necessary to make bold attempts and explorations in combination treatment regimens, so as to break through the current dilemma of ineffective standard treatment for some patients and bring benefits to these mCRC patients
.

Case essentials

The patient was a case of differentiated adenocarcinoma of the colon (cT4bN1bM0, stage III.
B), type
MSS.
Radical colon cancer surgery was given during initial treatment, but unfortunately patients who did not have adjuvant therapy after surgery developed rapid liver metastasis
in a short period of time.
In first- and second-line treatment, patients were insensitive to chemotherapy and had poor overall benefit, achieving a progression-free survival (PFS)
of 6.
3 months.
In the third-line treatment, based on the patient's genetic test results: TP53 and KRAS mutations occurred at the same time, combined with the third-line recommended treatment plan for CSCO colorectal cancer, the individualized treatment regimen of fruquintinib combined with sindilimab was selected for the patient, and the target lesion of the liver continued to shrink during the treatment process, and there were no adverse reactions throughout the process, achieving a survival benefit
of 12 months.
After the patient developed PD, TAS-102 combined with bevacizumab was selected for fourth-line treatment, but unfortunately the patient died of sudden convulsions
.

From the perspective of overall treatment, the patient progressed rapidly in the first and second line therapy, and the significant benefit from the anti-angiogenic combined immunotherapy of the third-line treatment reflected the excellent efficacy of anti-angiogenic combined immunotherapy in this MSS-type CRC patient, and provided reference for
other similar cases.
For most patients with MSS who cannot benefit from immunotherapy, anti-angiogenic combined immunotherapy has achieved initial results, and it is expected to continue to explore in follow-up treatment to bring better survival benefits
to MSS-type CRC patients.

References:

[1].
Xiao Y, Freeman GJ.
The microsatellite instable subset of colorectal cancer is a particularly good candidate for checkpoint blockade immunotherapy.
Cancer Discov.
2015 Jan; 5(1):16-8.

[2].
Dong ZY, Zhong WZ, Zhang XC, et al.
Potential Predictive Value of TP53 and KRAS Mutation Status for Response to PD-1 Blockade Immunotherapy in Lung Adenocarcinoma.
Clin Cancer Res.
2017 Jun 15; 23(12):3012-3024.

[3].
Ye Guo, Weijie Zhang, Jieer Ying, et al.
Preliminary results of a phase 1b study of fruquintinib plus sintilimab in advanced colorectal cancer.
2021 ASCO Abstract 2514.